BLOCK 3: IMM: (3.7) B-CELL ACTIVATION

B-cell Activation

• B-cell activation requires cross-linking of the B-cell receptor (BCR).
• The BCR complex consists of monomeric IgM bound to antigen, along with Igα and Igβ chains for intracellular signaling.
• Multivalent antigens with regularly arrayed epitopes on pathogen surfaces can bind to IgM and cluster BCRs.
• B-cell co-receptors, like CD19, synergize with BCR signaling.
• Cross-linking of BCR and co-receptor increases the strength and efficiency of intracellular signaling.
• Soluble antigens tagged with C3d can also activate B cells by cross-linking BCR and co-receptor.

B-cell Activation with T-cell Help

• Effective B-cell mediated immunity often requires help from CD4+ T follicular helper (TFH) cells.
• Naive B cells internalize antigen, process it, and present it to T cells via MHC class II.
• TFH cells recognize pathogen-derived peptides presented by MHC class II on B cells, leading to B cell activation.
• TFH cells synthesize CD40 ligand (CD40L) which interacts with B-cell CD40 receptors.
• TFH cells secrete cytokines like IL-21, which further contributes to B-cell activation.

B-cell Independent Activation

• T-cell independent activation of B cells (TI) occurs primarily in B-1 cells.
• TI antigens typically have dense and regular arrays of epitopes on pathogen surfaces, leading to strong BCR clustering and activation.
• TI activation does not require T-cell help, as the dense clustering of BCRs provides sufficient signaling.

Follicular Dendritic Cells (FDCs)

• FDCs in the B-cell area store intact antigens and display them to B cells.
• FDCs act as antigen-presenting cells for B-cell activation.
• FDCs express complement receptors (CR2) that bind antigens tagged with C3d.
• This tethering of antigens to FDCs facilitates their presentation to naive B cells.

B-cell Migration and Primary Focus

• Antigen-activated B cells move to the T-cell area to find a TFH cell.
• Activated B and TFH cells, forming a cognate pair, move to the medullary cords.
• This area is known as the primary focus of B-cell expansion.
• During this primary focus, B cells undergo clonal expansion and differentiation into IgM-secreting plasma cells.

Germinal Centers and Secondary Focus

• Some B cells from the primary focus return to the follicle, forming a germinal center.
• The germinal center represents the secondary focus of B-cell expansion.
• Germinal centers are sites where B cells undergo affinity maturation and isotype switching.

Germinal Center Anatomy

• Germinal centers are specialized microenvironments within the primary follicle.
• They are composed of rapidly dividing B cells called centroblasts, which form the dark zone.
• As centroblasts mature, they become non-dividing centrocytes, which form the light zone.
• FDCs in the light zone present antigens to centrocytes.
• TFH cells are present in the light zone and contribute to antigen-mediated selección of centrocytes.

Affinity Maturation

• Somatic hypermutation introduces mutations in the BCR genes of centroblasts.
• Centrocytes with BCRs that exhibit increased affinity for the antigen survive, while those with decreased affinity undergo apoptosis.
• This process drives affinity maturation of the B-cell response.

Isotype Switching

• TFH cells secrete cytokines that guide B-cell isotype switching.
• IL-4 promotes switching to IgE.
• IFN-γ promotes switching to IgG.
• IL-5 promotes switching to IgA.
• IL-10 and IL-21 promote both plasma cell and memory B cell differentiation.

Plasma Cell and Memory B Cell Differentiation

• TFH cells contribute to the differentiation of activated B cells into either plasma cells or memory B cells.
• IL-10 and IL-21 drive the differentiation process.

Ellen Vitetta

• Ellen Vitetta is a prominent immunologist who made significant contributions to our understanding of B-cell biology.

B cell negative selection

• B cells are selected against if they react to self‐antigen, removing any cells that react to self‐antigen.
• Cells that react to self-antigen are retained in the bone marrow, which contrasts with T cells where cells are killed directly.

B cell positive selection

• B cells are selected for if they can bind to antigen directly.
• T cells are also positively selected, but this occurs based on their ability to recognize self molecules.
• B cells go through negative selection before positive selection, whereas T cells go through positive selection before negative selection.
• After positive selection, B cells that can bind to antigen are allowed to leave the bone marrow and circulate in the blood.

B cell receptor editing

• If a B cell reacts to self-antigen, the B cell receptor can be edited to change its specificity.

B cell types

• B2 cells are the most common type and they are active in the immune response.
• B2 cells have a broad range of epitopes that they can recognize due to the rearrangement of their heavy and light chains during development.
• B2 cells respond more quickly to repeated exposure to an antigen due to a process called affinity maturation.
• Changes in immunoglobulin isotypes can happen due to a process called isotype switching.
• B2 cells are responsible for the formation of memory B cells.

Phases of development

• The first phase of B cell development is defined by the process of receptor editing and focuses on selection processes.
• The process of receptor editing happens before positive selection.
• The second phase of development happens in secondary lymphoid tissues.
• The third phase of development happens in the periphery.

B cell maturation

• Immature B cells express IgM and leave the bone marrow.
• Mature B cells express both IgM and IgD.
• B cells circulate in the blood and lymph.
• They will re-enter secondary lymphoid tissues to initiate an immune response.

This quiz covers the mechanisms of B-cell activation, including the role of B-cell receptors and co-receptors in signaling. It also explores the importance of CD4+ T follicular helper cells in mediating an effective immune response. Test your knowledge on the interactions between B cells and T cells in the adaptive immune system.